1. Field of the Invention
This invention is directed to methods for inhibiting immune responses or cellular interactions in mammals by the administration thereto of one or more lectin derived carbohydrate binding peptides. In particular, this invention is directed to methods for the suppression of inflammatory responses, induction of tolerance to antigens, modulation of the induction of immune responses to antigens, and the inhibition of cell adhesion in mammals by the administration of one or more carbohydrate binding peptides. The lectin derived carbohydrate binding peptides employed herein are preferably fragments of the S2 or S3 subunits of the pertussis toxin expressed by Bordetella pertussis or functionally equivalent variants thereof.
2. References
The following references are cited in this application as superscript numbers at the relevant portion of the application:
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The disclosure of all publications, patents and patent applications cited in this application are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
Important processes involving mammalian cells, such as growth, locomotion, morphological development, and differentiation are partially controlled by extracellular signals acting upon the cells' surfaces.sup.1-3. While some external stimuli reach the cell via extracellular fluids, other signals are received from neighboring or approaching cell surfaces and exert their effects through direct cell-cell contact.sup.4,5.
Evidence suggests that specific cell-surface receptors can "sense" a molecular signal of an apposing cell via specific binding, and biochemical mechanisms exist to translate that binding into a cellular response. For example, complex cell-surface interactions are believed to help direct processes such as binding of pathogens to target tissues.sup.6,7, sperm-egg binding.sup.8, interactions among cells in the immune system.sup.9,10, and recognition of cells during embryonic development.sup.11. In addition, defects in cell-cell recognition are thought to underlie the uncontrolled cell growth and motility which characterize neoplastic transformation and metastasis.sup.12,13.
Other evidence suggests that cell-recognition processes are mediated by carbohydrate chains or glycan portions of glycoconjugatest.sup.4,14-16. For example, the binding of the surface glycoconjugates of one cell to the complementary carbohydrate-binding proteins (lectins) on another cell can result in the initiation of a specific interaction.
One important group of carbohydrate-binding proteins are selectin (LEC-CAM) proteins (Lectin+EGF+complementary Regulatory Domain-Cell Adhesion Molecules). These or functionally similar proteins or lectins are believed to play a critical role in immune responses (including inflammatory responses) through mediation of cell-cell contact and through extra-vasation of leucocytes.sup.17-22. Specific carbohydrate ligands have been identified as part of the putative receptor structures for selectin proteins and other lectins.sup.17-25. The structures identified include oligosaccharide glycosides containing terminally linked .alpha.-sialic acid(2.fwdarw.6).beta.Gal- and .alpha.-sialic acid(2.fwdarw.3).beta.Gal-groups. The use of oligosaccharides and derivatives thereof having such terminally linked groups for controlling inflammation, immunosuppression, etc. by interacting with selectin proteins and/or other lectins has been disclosed.sup.26-29,35-41.
Likewise, peptides derived from the selectin GMP-140 which inhibit binding of GMP-140 and other selectins to leukocytes, presumably by interfering with the binding of the GMP-selectin protein with the carbohydrate receptor on the leukocyte, have also been disclosed as being useful in suppressing an immune response.sup.29. Similarly, other peptides are also known to be potent modulators of neutrophil functions.sup.48.
Pertussis toxin (PT).sup.42, a virulence factor produced by the organism Bordetella pertussis--the etiological agent of whooping cough, is known to bind to glycoprotein receptors which terminate in sialyllactosamine sugar sequences.sup.43,44 and we have previously shown that this protein is useful in suppressing mammalian immune responses and cellular adhesion.sup.45. PT's binding specificity has been shown to be similar to that of the plant lectins from Sambucus nigra (SNA) and Maackia amurensis (MAL).sup.25, which bind with high affinity to sialic acid-containing glycoconjugates.sup.46,47 and which have also been shown as possessing immunomodulating properties.sup.45.
However, the use of proteins or large molecular weight polypeptides in inhibiting immune responses or cellular interactions in mammals suffers from several drawbacks, including the fact that they are difficult to produce in large quantities in pure form; that they tend to produce adverse affects when repeatedly administered to a mammal; that they can contain infectious agents or toxic substances which are contra-indications to mammalian administration; and, that it is difficult to modify the pharmokinetic properties of such proteins to improve their efficacy.
In view of the above, the use of peptides having lectin-like binding properties for terminal .alpha.Neu5Ac(2.fwdarw.3).beta.Gal- and .alpha.Neu5Ac(2.fwdarw.6).beta.Gal- groups would be particularly beneficial for use in inhibiting immune responses and cellular interactions in mammals as compared to the administration of proteins such the pertussis toxin and the lectins derived from SNA and MAL because such peptides would mitigate the problems associated with the administration of proteins and large molecular weight polypeptides to mammals.